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Abstraction Layers for Scalable Microfluidic Biocomputers William Thies*, J.P. Urbanski †, Todd Thorsen † and Saman Amarasinghe * * Computer Science and.

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Presentation on theme: "Abstraction Layers for Scalable Microfluidic Biocomputers William Thies*, J.P. Urbanski †, Todd Thorsen † and Saman Amarasinghe * * Computer Science and."— Presentation transcript:

1 Abstraction Layers for Scalable Microfluidic Biocomputers William Thies*, J.P. Urbanski †, Todd Thorsen † and Saman Amarasinghe * * Computer Science and Artificial Intelligence Laboratory Hatsopoulos Microfluids Laboratory Massachusetts Institute of Technology International Meeting on DNA Computing – June 8, 2006 †

2 Biocomputing Demands Complex Protocols Complex biology experiments have many hazards –Time-consuming laboratory protocols –Risk of human error –Expensive reagents and equipment Biocomputing: complexity grows with problem size –20-variable 3-SAT problem: >96 hours to complete –Larger instances will be even more challenging –Need a scalable approach Our approach: Write protocols as programs, run on microfluidic chips –Write once, run anywhere –This talk: how do you “program” a biological protocol? [Adleman02]

3 Microfluidic Chips Idea: a whole biology lab on a single chip –Input/output –Sensors: luminescence, pH, glucose, etc. –Actuators: mixing, PCR, electrophoresis, cell lysis, etc. Benefits: –Small sample volumes –High throughput –Geometrical manipulation Applications: –Biochemistry - Cell biology –Biological computing [Farfel/Stefanovic] [Grover/Mathies] [Gehani/Reif] [Livstone/Landweber][van Noort][McCaskill] [Somei/Kaneda/Fujii/Murata] 1 mm 10x real-time

4 Moore’s Law of Microfluidics: Valve Density Doubles Every 4 Months Source: Fluidigm Corporation (http://www.fluidigm.com/images/mlaw_lg.jpg)

5 Moore’s Law of Microfluidics: Valve Density Doubles Every 4 Months Source: Fluidigm Corporation (http://www.fluidigm.com/didIFC.htm)

6 How to Conduct Experiments? Lab-on-a-chip Lab bench Human director Current choices: Design custom microfluidic chip to automatically perform your experiment Orchestrate every valve operation by hand (e.g., using Labview) Two choices: Design custom microfluidic chip to automatically perform your experiment

7 Programmable Solution Example: Gradient generation Hidden from programmer: –Location of fluids –Details of mixing, I/O –Logic of valve control –Timing of chip operations 450 Valve Operations Fluid yellow = input (0); Fluid blue = input(1); for (int i=0; i<=4; i++) { mix(yellow, 1-i/4, blue, i/4); }

8 Programmable Solution Example: Gradient generation Hidden from programmer: –Location of fluids –Details of mixing, I/O –Logic of valve control –Timing of chip operations setValve(0, HIGH); setValve(1, HIGH); setValve(2, LOW); setValve(3, HIGH); setValve(4, LOW); setValve(5, LOW); setValve(6, HIGH); setValve(7, LOW); setValve(8, LOW); setValve(9, HIGH); setValve(10, LOW); setValve(11, HIGH); setValve(12, LOW); setValve(13, HIGH); setValve(14, LOW); setValve(15, HIGH); setValve(16, LOW); setValve(17, LOW); setValve(18, LOW); setValve(19, LOW); wait(2000); setValve(14, HIGH); setValve(2, LOW); wait(1000); setValve(4, HIGH); setValve(12, LOW); setValve(16, HIGH); setValve(18, HIGH); setValve(19, LOW); wait(2000); 450 Valve Operations Fluid yellow = input (0); Fluid blue = input(1); for (int i=0; i<=4; i++) { mix(yellow, 1-i/4, blue, i/4); }

9 450 Valve Operations Programmable Solution Example: Gradient generation Hidden from programmer: –Location of fluids –Details of mixing, I/O –Logic of valve control –Timing of chip operations setValve(0, HIGH); setValve(1, HIGH); setValve(2, LOW); setValve(3, HIGH); setValve(4, LOW); setValve(5, LOW); setValve(6, HIGH); setValve(7, LOW); setValve(8, LOW); setValve(9, HIGH); setValve(10, LOW); setValve(11, HIGH); setValve(12, LOW); setValve(13, HIGH); setValve(14, LOW); setValve(15, HIGH); setValve(16, LOW); setValve(17, LOW); setValve(18, LOW); setValve(19, LOW); wait(2000); setValve(14, HIGH); setValve(2, LOW); wait(1000); setValve(4, HIGH); setValve(12, LOW); setValve(16, HIGH); setValve(18, HIGH); setValve(19, LOW); wait(2000); setValve(14, HIGH); setValve(2, LOW); wait(1000); setValve(4, HIGH); setValve(12, LOW); setValve(16, HIGH); setValve(18, HIGH); setValve(19, LOW); wait(2000); setValve(0, LOW); setValve(1, LOW); setValve(2, LOW); setValve(3, HIGH); setValve(4, LOW); setValve(5, HIGH); setValve(6, HIGH); setValve(7, LOW); setValve(8, LOW); setValve(9, HIGH); setValve(10, HIGH); setValve(11, LOW); setValve(12, LOW); setValve(13, LOW); setValve(14, LOW); setValve(15, HIGH); setValve(16, HIGH); setValve(17, LOW); setValve(18, HIGH); setValve(19, LOW); setValve(0, HIGH); setValve(1, HIGH); setValve(2, LOW); setValve(3, HIGH); setValve(4, LOW); setValve(5, LOW); setValve(6, HIGH); setValve(7, LOW); setValve(8, LOW); setValve(9, HIGH); setValve(10, LOW); setValve(11, HIGH); setValve(12, LOW); setValve(13, HIGH); setValve(14, LOW); setValve(15, HIGH); setValve(16, LOW); setValve(17, LOW); setValve(18, LOW); setValve(19, LOW); wait(2000); setValve(14, HIGH); setValve(2, LOW); wait(1000); setValve(4, HIGH); setValve(12, LOW); setValve(16, HIGH); setValve(18, HIGH); setValve(19, LOW); wait(2000); setValve(14, HIGH); setValve(2, LOW); wait(1000); setValve(4, HIGH); setValve(12, LOW); setValve(16, HIGH); setValve(18, HIGH); setValve(19, LOW); wait(2000); setValve(0, LOW); setValve(1, LOW); setValve(2, LOW); setValve(3, HIGH); setValve(4, LOW); setValve(5, HIGH); setValve(6, HIGH); setValve(7, LOW); setValve(8, LOW); setValve(9, HIGH); setValve(10, HIGH); setValve(11, LOW); setValve(12, LOW); setValve(13, LOW); setValve(14, LOW); setValve(15, HIGH); setValve(16, HIGH); setValve(17, LOW); setValve(18, HIGH); setValve(19, LOW); setValve(0, HIGH); setValve(1, HIGH); setValve(2, LOW); setValve(3, HIGH); setValve(4, LOW); setValve(5, LOW); setValve(6, HIGH); setValve(7, LOW); setValve(8, LOW); setValve(9, HIGH); setValve(10, LOW); setValve(11, HIGH); setValve(12, LOW); setValve(13, HIGH); setValve(14, LOW); setValve(15, HIGH); setValve(16, LOW); setValve(17, LOW); setValve(18, LOW); setValve(19, LOW); wait(2000); setValve(14, HIGH); setValve(2, LOW); wait(1000); setValve(4, HIGH); setValve(12, LOW); setValve(16, HIGH); setValve(18, HIGH); setValve(19, LOW); wait(2000); setValve(14, HIGH); setValve(2, LOW); wait(1000); setValve(4, HIGH); setValve(12, LOW); setValve(16, HIGH); setValve(18, HIGH); setValve(19, LOW); wait(2000); setValve(0, LOW); setValve(1, LOW); setValve(2, LOW); setValve(3, HIGH); setValve(4, LOW); setValve(5, HIGH); setValve(6, HIGH); setValve(7, LOW); setValve(8, LOW); setValve(9, HIGH); setValve(10, HIGH); setValve(11, LOW); setValve(12, LOW); setValve(13, LOW); setValve(14, LOW); setValve(15, HIGH); setValve(16, HIGH); setValve(17, LOW); setValve(18, HIGH); setValve(19, LOW); setValve(0, HIGH); setValve(1, HIGH); setValve(2, LOW); setValve(3, HIGH); setValve(4, LOW); setValve(5, LOW); setValve(6, HIGH); setValve(7, LOW); setValve(8, LOW); setValve(9, HIGH); setValve(10, LOW); setValve(11, HIGH); setValve(12, LOW); setValve(13, HIGH); setValve(14, LOW); setValve(15, HIGH); setValve(16, LOW); setValve(17, LOW); setValve(18, LOW); setValve(19, LOW); wait(2000); setValve(14, HIGH); setValve(2, LOW); wait(1000); setValve(4, HIGH); setValve(12, LOW); setValve(16, HIGH); setValve(18, HIGH); setValve(19, LOW); wait(2000); setValve(14, HIGH); setValve(2, LOW); wait(1000); setValve(4, HIGH); setValve(12, LOW); setValve(16, HIGH); setValve(18, HIGH); setValve(19, LOW); wait(2000); setValve(0, LOW); setValve(1, LOW); setValve(2, LOW); setValve(3, HIGH); setValve(4, LOW); setValve(5, HIGH); setValve(6, HIGH); setValve(7, LOW); setValve(8, LOW); setValve(9, HIGH); setValve(10, HIGH); setValve(11, LOW); setValve(12, LOW); setValve(13, LOW); setValve(14, LOW); setValve(15, HIGH); setValve(16, HIGH); setValve(17, LOW); setValve(18, HIGH); setValve(19, LOW); setValve(0, HIGH); setValve(1, HIGH); setValve(2, LOW); setValve(3, HIGH); setValve(4, LOW); setValve(5, LOW); setValve(6, HIGH); setValve(7, LOW); setValve(8, LOW); setValve(9, HIGH); setValve(10, LOW); setValve(11, HIGH); setValve(12, LOW); setValve(13, HIGH); setValve(14, LOW); setValve(15, HIGH); setValve(16, LOW); setValve(17, LOW); setValve(18, LOW); setValve(19, LOW); wait(2000); setValve(14, HIGH); setValve(2, LOW); wait(1000); setValve(4, HIGH); setValve(12, LOW); setValve(16, HIGH); setValve(18, HIGH); setValve(19, LOW); wait(2000); setValve(14, HIGH); setValve(2, LOW); wait(1000); setValve(4, HIGH); setValve(12, LOW); setValve(16, HIGH); setValve(18, HIGH); setValve(19, LOW); wait(2000); setValve(0, LOW); setValve(1, LOW); setValve(2, LOW); setValve(3, HIGH); setValve(4, LOW); setValve(5, HIGH); setValve(6, HIGH); setValve(7, LOW); setValve(8, LOW); setValve(9, HIGH); setValve(10, HIGH); setValve(11, LOW); setValve(12, LOW); setValve(13, LOW); setValve(14, LOW); setValve(15, HIGH); setValve(16, HIGH); setValve(17, LOW); setValve(18, HIGH); setValve(19, LOW); setValve(0, HIGH); setValve(1, HIGH); setValve(2, LOW); setValve(3, HIGH); setValve(4, LOW); setValve(5, LOW); setValve(6, HIGH); setValve(7, LOW); setValve(8, LOW); setValve(9, HIGH); setValve(10, LOW); setValve(11, HIGH); setValve(12, LOW); setValve(13, HIGH); setValve(14, LOW); setValve(15, HIGH); setValve(16, LOW); setValve(17, LOW); setValve(18, LOW); setValve(19, LOW); wait(2000); setValve(14, HIGH); setValve(2, LOW); wait(1000); setValve(4, HIGH); setValve(12, LOW); setValve(16, HIGH); setValve(18, HIGH); setValve(19, LOW); wait(2000); setValve(14, HIGH); setValve(2, LOW); wait(1000); setValve(4, HIGH); setValve(12, LOW); setValve(16, HIGH); setValve(18, HIGH); setValve(19, LOW); wait(2000); setValve(0, LOW); setValve(1, LOW); setValve(2, LOW); setValve(3, HIGH); setValve(4, LOW); setValve(5, HIGH); setValve(6, HIGH); setValve(7, LOW); setValve(8, LOW); setValve(9, HIGH); setValve(10, HIGH); setValve(11, LOW); setValve(12, LOW); setValve(13, LOW); setValve(14, LOW); setValve(15, HIGH); setValve(16, HIGH); setValve(17, LOW); setValve(18, HIGH); setValve(19, LOW); setValve(0, HIGH); setValve(1, HIGH); setValve(2, LOW); setValve(3, HIGH); setValve(4, LOW); setValve(5, LOW); setValve(6, HIGH); setValve(7, LOW); setValve(8, LOW); setValve(9, HIGH); setValve(10, LOW); setValve(11, HIGH); setValve(12, LOW); setValve(13, HIGH); setValve(14, LOW); setValve(15, HIGH); setValve(16, LOW); setValve(17, LOW); setValve(18, LOW); setValve(19, LOW); wait(2000); setValve(14, HIGH); setValve(2, LOW); wait(1000); setValve(4, HIGH); setValve(12, LOW); setValve(16, HIGH); setValve(18, HIGH); setValve(19, LOW); wait(2000); setValve(14, HIGH); setValve(2, LOW); wait(1000); setValve(4, HIGH); setValve(12, LOW); setValve(16, HIGH); setValve(18, HIGH); setValve(19, LOW); wait(2000); setValve(0, LOW); setValve(1, LOW); setValve(2, LOW); setValve(3, HIGH); setValve(4, LOW); setValve(5, HIGH); setValve(6, HIGH); setValve(7, LOW); setValve(8, LOW); setValve(9, HIGH); setValve(10, HIGH); setValve(11, LOW); setValve(12, LOW); setValve(13, LOW); setValve(14, LOW); setValve(15, HIGH); setValve(16, HIGH); setValve(17, LOW); setValve(18, HIGH); setValve(19, LOW); setValve(0, HIGH); setValve(1, HIGH); setValve(2, LOW); setValve(3, HIGH); setValve(4, LOW); setValve(5, LOW); setValve(6, HIGH); setValve(7, LOW); setValve(8, LOW); setValve(9, HIGH); setValve(10, LOW); setValve(11, HIGH); setValve(12, LOW); setValve(13, HIGH); setValve(14, LOW); setValve(15, HIGH); setValve(16, LOW); setValve(17, LOW); setValve(18, LOW); setValve(19, LOW); wait(2000); setValve(14, HIGH); setValve(2, LOW); wait(1000); setValve(4, HIGH); setValve(12, LOW); setValve(16, HIGH); setValve(18, HIGH); setValve(19, LOW); wait(2000); setValve(14, HIGH); setValve(2, LOW); wait(1000); setValve(4, HIGH); setValve(12, LOW); setValve(16, HIGH); setValve(18, HIGH); setValve(19, LOW); wait(2000); setValve(0, LOW); setValve(1, LOW); setValve(2, LOW); setValve(3, HIGH); setValve(4, LOW); setValve(5, HIGH); setValve(6, HIGH); setValve(7, LOW); setValve(8, LOW); setValve(9, HIGH); setValve(10, HIGH); setValve(11, LOW); setValve(12, LOW); setValve(13, LOW); setValve(14, LOW); setValve(15, HIGH); setValve(16, HIGH); setValve(17, LOW); setValve(18, HIGH); setValve(19, LOW); Fluid yellow = input (0); Fluid blue = input(1); for (int i=0; i<=4; i++) { mix(yellow, 1-i/4, blue, i/4); }

10 Fluidic Abstraction Layers Fluidic Instruction Set Architecture (ISA) - primitives for I/O, storage, transport, mixing Protocol Description Language - readable code with high-level mixing ops Abstract Computational Problem - SAT formula, max-clique graph C x86 Mathematica Pentium III, Pentium IV Silicon Analog chip 1 chip 2 chip 3

11 Fluidic Abstraction Layers Benefits: –Portability –Division of labor –Scalability –Expressivity Fluidic Instruction Set Architecture (ISA) - primitives for I/O, storage, transport, mixing Protocol Description Language - readable code with high-level mixing ops Abstract Computational Problem - SAT formula, max-clique graph chip 1 chip 2 chip 3

12 Fluidic Abstraction Layers Benefits: –Portability –Division of labor –Scalability –Expressivity Fluidic Instruction Set Architecture (ISA) - primitives for I/O, storage, transport, mixing Protocol Description Language - readable code with high-level mixing ops Abstract Computational Problem - SAT formula, max-clique graph chip 1 chip 2 chip 3

13 Abstraction 1: Digital Architecture Recent chips can control independent fluid samples –Droplet-based samples –Continuous-flow samples –Microfluidic latches In abstract machine, all samples have unit volume –Input/output a sample –Store a sample –Operate on a sample [Fair et al.] [Urbanski et al.]

14 Abstraction 2: Mix Instruction Microfluidic chips have various mixing technologies –Electrokinetic mixing –Droplet mixing –Rotary mixing Common attributes: –Ability to mix two samples in equal proportions, store result Fluidic ISA: mix (int src 1, int src 2, int dst) –Ex: mix(1, 2, 3) –To allow for lossy transport, only 1 unit of mixture retained [Quake et al.] [Fair et al.] [Levitan et al.] Storage Cells 1 2 3 4 Mixer

15 Gradient Generation in Fluidic ISA 450 Valve Operations setValve(0, HIGH); setValve(1, HIGH); setValve(2, LOW); setValve(3, HIGH); setValve(4, LOW); setValve(5, LOW); setValve(6, HIGH); setValve(7, LOW); setValve(8, LOW); setValve(9, HIGH); setValve(10, LOW); setValve(11, HIGH); setValve(12, LOW); setValve(13, HIGH); setValve(14, LOW); setValve(15, HIGH); setValve(16, LOW); setValve(17, LOW); setValve(18, LOW); setValve(19, LOW); wait(2000); setValve(14, HIGH); setValve(2, LOW); wait(1000); setValve(4, HIGH); setValve(12, LOW); setValve(16, HIGH); setValve(18, HIGH); setValve(19, LOW); wait(2000); setValve(14, HIGH); setValve(2, LOW); wait(1000); setValve(4, HIGH); setValve(12, LOW); setValve(16, HIGH); setValve(18, HIGH); setValve(19, LOW); wait(2000); setValve(0, LOW); setValve(1, LOW); setValve(2, LOW); setValve(3, HIGH); setValve(4, LOW); setValve(5, HIGH); setValve(6, HIGH); setValve(7, LOW); setValve(8, LOW); setValve(9, HIGH); setValve(10, HIGH); setValve(11, LOW); setValve(12, LOW); setValve(13, LOW); setValve(14, LOW); setValve(15, HIGH); setValve(16, HIGH); setValve(17, LOW); setValve(18, HIGH); setValve(19, LOW); setValve(0, HIGH); setValve(1, HIGH); setValve(2, LOW); setValve(3, HIGH); setValve(4, LOW); setValve(5, LOW); setValve(6, HIGH); setValve(7, LOW); setValve(8, LOW); setValve(9, HIGH); setValve(10, LOW); setValve(11, HIGH); setValve(12, LOW); setValve(13, HIGH); setValve(14, LOW); setValve(15, HIGH); setValve(16, LOW); setValve(17, LOW); setValve(18, LOW); setValve(19, LOW); wait(2000); setValve(14, HIGH); setValve(2, LOW); wait(1000); setValve(4, HIGH); setValve(12, LOW); setValve(16, HIGH); setValve(18, HIGH); setValve(19, LOW); wait(2000); setValve(14, HIGH); setValve(2, LOW); wait(1000); setValve(4, HIGH); setValve(12, LOW); setValve(16, HIGH); setValve(18, HIGH); setValve(19, LOW); wait(2000); setValve(0, LOW); setValve(1, LOW); setValve(2, LOW); setValve(3, HIGH); setValve(4, LOW); setValve(5, HIGH); setValve(6, HIGH); setValve(7, LOW); setValve(8, LOW); setValve(9, HIGH); setValve(10, HIGH); setValve(11, LOW); setValve(12, LOW); setValve(13, LOW); setValve(14, LOW); setValve(15, HIGH); setValve(16, HIGH); setValve(17, LOW); setValve(18, HIGH); setValve(19, LOW); setValve(0, HIGH); setValve(1, HIGH); setValve(2, LOW); setValve(3, HIGH); setValve(4, LOW); setValve(5, LOW); setValve(6, HIGH); setValve(7, LOW); setValve(8, LOW); setValve(9, HIGH); setValve(10, LOW); setValve(11, HIGH); setValve(12, LOW); setValve(13, HIGH); setValve(14, LOW); setValve(15, HIGH); setValve(16, LOW); setValve(17, LOW); setValve(18, LOW); setValve(19, LOW); wait(2000); setValve(14, HIGH); setValve(2, LOW); wait(1000); setValve(4, HIGH); setValve(12, LOW); setValve(16, HIGH); setValve(18, HIGH); setValve(19, LOW); wait(2000); setValve(14, HIGH); setValve(2, LOW); wait(1000); setValve(4, HIGH); setValve(12, LOW); setValve(16, HIGH); setValve(18, HIGH); setValve(19, LOW); wait(2000); setValve(0, LOW); setValve(1, LOW); setValve(2, LOW); setValve(3, HIGH); setValve(4, LOW); setValve(5, HIGH); setValve(6, HIGH); setValve(7, LOW); setValve(8, LOW); setValve(9, HIGH); setValve(10, HIGH); setValve(11, LOW); setValve(12, LOW); setValve(13, LOW); setValve(14, LOW); setValve(15, HIGH); setValve(16, HIGH); setValve(17, LOW); setValve(18, HIGH); setValve(19, LOW); setValve(0, HIGH); setValve(1, HIGH); setValve(2, LOW); setValve(3, HIGH); setValve(4, LOW); setValve(5, LOW); setValve(6, HIGH); setValve(7, LOW); setValve(8, LOW); setValve(9, HIGH); setValve(10, LOW); setValve(11, HIGH); setValve(12, LOW); setValve(13, HIGH); setValve(14, LOW); setValve(15, HIGH); setValve(16, LOW); setValve(17, LOW); setValve(18, LOW); setValve(19, LOW); wait(2000); setValve(14, HIGH); setValve(2, LOW); wait(1000); setValve(4, HIGH); setValve(12, LOW); setValve(16, HIGH); setValve(18, HIGH); setValve(19, LOW); wait(2000); setValve(14, HIGH); setValve(2, LOW); wait(1000); setValve(4, HIGH); setValve(12, LOW); setValve(16, HIGH); setValve(18, HIGH); setValve(19, LOW); wait(2000); setValve(0, LOW); setValve(1, LOW); setValve(2, LOW); setValve(3, HIGH); setValve(4, LOW); setValve(5, HIGH); setValve(6, HIGH); setValve(7, LOW); setValve(8, LOW); setValve(9, HIGH); setValve(10, HIGH); setValve(11, LOW); setValve(12, LOW); setValve(13, LOW); setValve(14, LOW); setValve(15, HIGH); setValve(16, HIGH); setValve(17, LOW); setValve(18, HIGH); setValve(19, LOW); setValve(0, HIGH); setValve(1, HIGH); setValve(2, LOW); setValve(3, HIGH); setValve(4, LOW); setValve(5, LOW); setValve(6, HIGH); setValve(7, LOW); setValve(8, LOW); setValve(9, HIGH); setValve(10, LOW); setValve(11, HIGH); setValve(12, LOW); setValve(13, HIGH); setValve(14, LOW); setValve(15, HIGH); setValve(16, LOW); setValve(17, LOW); setValve(18, LOW); setValve(19, LOW); wait(2000); setValve(14, HIGH); setValve(2, LOW); wait(1000); setValve(4, HIGH); setValve(12, LOW); setValve(16, HIGH); setValve(18, HIGH); setValve(19, LOW); wait(2000); setValve(14, HIGH); setValve(2, LOW); wait(1000); setValve(4, HIGH); setValve(12, LOW); setValve(16, HIGH); setValve(18, HIGH); setValve(19, LOW); wait(2000); setValve(0, LOW); setValve(1, LOW); setValve(2, LOW); setValve(3, HIGH); setValve(4, LOW); setValve(5, HIGH); setValve(6, HIGH); setValve(7, LOW); setValve(8, LOW); setValve(9, HIGH); setValve(10, HIGH); setValve(11, LOW); setValve(12, LOW); setValve(13, LOW); setValve(14, LOW); setValve(15, HIGH); setValve(16, HIGH); setValve(17, LOW); setValve(18, HIGH); setValve(19, LOW); setValve(0, HIGH); setValve(1, HIGH); setValve(2, LOW); setValve(3, HIGH); setValve(4, LOW); setValve(5, LOW); setValve(6, HIGH); setValve(7, LOW); setValve(8, LOW); setValve(9, HIGH); setValve(10, LOW); setValve(11, HIGH); setValve(12, LOW); setValve(13, HIGH); setValve(14, LOW); setValve(15, HIGH); setValve(16, LOW); setValve(17, LOW); setValve(18, LOW); setValve(19, LOW); wait(2000); setValve(14, HIGH); setValve(2, LOW); wait(1000); setValve(4, HIGH); setValve(12, LOW); setValve(16, HIGH); setValve(18, HIGH); setValve(19, LOW); wait(2000); setValve(14, HIGH); setValve(2, LOW); wait(1000); setValve(4, HIGH); setValve(12, LOW); setValve(16, HIGH); setValve(18, HIGH); setValve(19, LOW); wait(2000); setValve(0, LOW); setValve(1, LOW); setValve(2, LOW); setValve(3, HIGH); setValve(4, LOW); setValve(5, HIGH); setValve(6, HIGH); setValve(7, LOW); setValve(8, LOW); setValve(9, HIGH); setValve(10, HIGH); setValve(11, LOW); setValve(12, LOW); setValve(13, LOW); setValve(14, LOW); setValve(15, HIGH); setValve(16, HIGH); setValve(17, LOW); setValve(18, HIGH); setValve(19, LOW); setValve(0, HIGH); setValve(1, HIGH); setValve(2, LOW); setValve(3, HIGH); setValve(4, LOW); setValve(5, LOW); setValve(6, HIGH); setValve(7, LOW); setValve(8, LOW); setValve(9, HIGH); setValve(10, LOW); setValve(11, HIGH); setValve(12, LOW); setValve(13, HIGH); setValve(14, LOW); setValve(15, HIGH); setValve(16, LOW); setValve(17, LOW); setValve(18, LOW); setValve(19, LOW); wait(2000); setValve(14, HIGH); setValve(2, LOW); wait(1000); setValve(4, HIGH); setValve(12, LOW); setValve(16, HIGH); setValve(18, HIGH); setValve(19, LOW); wait(2000); setValve(14, HIGH); setValve(2, LOW); wait(1000); setValve(4, HIGH); setValve(12, LOW); setValve(16, HIGH); setValve(18, HIGH); setValve(19, LOW); wait(2000); setValve(0, LOW); setValve(1, LOW); setValve(2, LOW); setValve(3, HIGH); setValve(4, LOW); setValve(5, HIGH); setValve(6, HIGH); setValve(7, LOW); setValve(8, LOW); setValve(9, HIGH); setValve(10, HIGH); setValve(11, LOW); setValve(12, LOW); setValve(13, LOW); setValve(14, LOW); setValve(15, HIGH); setValve(16, HIGH); setValve(17, LOW); setValve(18, HIGH); setValve(19, LOW); setValve(0, HIGH); setValve(1, HIGH); setValve(2, LOW); setValve(3, HIGH); setValve(4, LOW); setValve(5, LOW); setValve(6, HIGH); setValve(7, LOW); setValve(8, LOW); setValve(9, HIGH); setValve(10, LOW); setValve(11, HIGH); setValve(12, LOW); setValve(13, HIGH); setValve(14, LOW); setValve(15, HIGH); setValve(16, LOW); setValve(17, LOW); setValve(18, LOW); setValve(19, LOW); wait(2000); setValve(14, HIGH); setValve(2, LOW); wait(1000); setValve(4, HIGH); setValve(12, LOW); setValve(16, HIGH); setValve(18, HIGH); setValve(19, LOW); wait(2000); setValve(14, HIGH); setValve(2, LOW); wait(1000); setValve(4, HIGH); setValve(12, LOW); setValve(16, HIGH); setValve(18, HIGH); setValve(19, LOW); wait(2000); setValve(0, LOW); setValve(1, LOW); setValve(2, LOW); setValve(3, HIGH); setValve(4, LOW); setValve(5, HIGH); setValve(6, HIGH); setValve(7, LOW); setValve(8, LOW); setValve(9, HIGH); setValve(10, HIGH); setValve(11, LOW); setValve(12, LOW); setValve(13, LOW); setValve(14, LOW); setValve(15, HIGH); setValve(16, HIGH); setValve(17, LOW); setValve(18, HIGH); setValve(19, LOW); input(0, 0); input(1, 1); input(0, 2); mix(1, 2, 3); input(0, 2); mix(2, 3, 1); input(1, 3); input(0, 4); mix(3, 4, 2); input(1, 3); input(0, 4); mix(3, 4, 5); input(1, 4); mix(4, 5, 3); mix(0, 4); Direct Control - 450 valve actuations - only works on 1 chip Fluidic ISA - 15 instructions - portable across chips abstraction

16 Implementation: Oil-Driven Chip InputsStorage CellsBackground PhaseWash PhaseMixing Chip 128Oil—Rotary

17 Implementation: Oil-Driven Chip InputsStorage CellsBackground PhaseWash PhaseMixing Chip 128Oil—Rotary mix (S 1, S 2, D) { 1. Load S 1 2. Load S 2 3. Rotary mixing 4. Store into D } 50x real-time

18 Implementation 2: Air-Driven Chip InputsStorage CellsBackground PhaseWash PhaseMixing Chip 128Oil—Rotary Chip 2432AirWaterIn channels

19 Implementation 2: Air-Driven Chip mix (S 1, S 2, D) { 1. Load S 1 2. Load S 2 3. Mix / Store into D 4. Wash S 1 5. Wash S 2 } InputsStorage CellsBackground PhaseWash PhaseMixing Chip 128Oil—Rotary Chip 2432AirWaterIn channels 50x real-time

20 Abstraction Layers Fluidic Instruction Set Architecture (ISA) - primitives for I/O, storage, transport, mixing Protocol Description Language - readable code with high-level mixing ops Abstract Computational Problem - SAT formula, max-clique graph chip 1 chip 2 chip 3

21 Fluid[] out = new Fluid[8]; Fluid yellow, blue, green; out[0] = input(0); yellow = input(0); blue = input(1); green = mix(yellow, blue); yellow = input(0); out[1] = mix(yellow, green); yellow = input(0); blue = input(1); out[2] = mix(yellow, blue); yellow = input(0); blue = input(1); green = mix(yellow, blue); blue = input(1); out[3] = mix(blue, green); out[4] = input(1); Abstraction 1: Managing Fluid Storage Programmer uses location-independent Fluid variables –Runtime system assigns & tracks location of each Fluid –Comparable to automatic memory management (e.g., Java) Fluidic ISA 1. Storage Management input(0, 0); input(1, 1); input(0, 2); mix(1, 2, 3); input(0, 2); mix(2, 3, 1); input(1, 3); input(0, 4); mix(3, 4, 2); input(1, 3); input(0, 4); mix(3, 4, 5); input(1, 4); mix(4, 5, 3); mix(0, 4);

22 Fluid[] out = new Fluid[8]; Fluid yellow, blue, green; out[0] = input(0); yellow = input(0); blue = input(1); green = mix(yellow, blue); yellow = input(0); out[1] = mix(yellow, green); yellow = input(0); blue = input(1); out[2] = mix(yellow, blue); yellow = input(0); blue = input(1); green = mix(yellow, blue); blue = input(1); out[3] = mix(blue, green); out[4] = input(1);

23 Fluid[] out = new Fluid[8]; Fluid yellow = input(0); Fluid blue = input(1); Fluid green = mix(yellow, blue); out[0] = yellow; out[1] = mix(yellow, green); out[2] = green; out[3] = mix(blue, green); out[4] = blue; Fluid[] out = new Fluid[8]; Fluid yellow, blue, green; out[0] = input(0); yellow = input(0); blue = input(1); green = mix(yellow, blue); yellow = input(0); out[1] = mix(yellow, green); yellow = input(0); blue = input(1); out[2] = mix(yellow, blue); yellow = input(0); blue = input(1); green = mix(yellow, blue); blue = input(1); out[3] = mix(blue, green); out[4] = input(1); Abstraction 2: Fluid Re-Generation 2. Fluid Re-Generation Programmer may use a Fluid variable multiple times –Each time, a physical Fluid is consumed on-chip –Runtime system re-generates Fluids from computation history

24 Fluid[] out = new Fluid[8]; Fluid yellow = input(0); Fluid blue = input(1); Fluid green = mix(yellow, blue); out[0] = yellow; out[1] = mix(yellow, green); out[2] = green; out[3] = mix(blue, green); out[4] = blue; 2. Fluid Re-Generation

25 Abstraction 3: Arbitrary Mixing Allows mixing fluids in any proportion, not just 50/50 –Fluid mix (Fluid F 1, float p 1, Fluid f 2, float F 2 )  Returns Fluid that is p 1 parts F 1 and p 2 parts F 2 –Runtime system translates to 50/50 mixes in Fluidic ISA –Note: some mixtures only reachable within error tolerance  Fluid[] out = new Fluid[8]; Fluid yellow = input (0); Fluid blue = input (1); out[0] = yellow; out[1] = mix(yellow, 3/4, blue, 1/4); out[2] = mix(yellow, 1/2, blue, 1/2); out[3] = mix(yellow, 1/4, blue, 3/4); out[4] = blue; 3. Arbitrary Mixing Fluid[] out = new Fluid[8]; Fluid yellow = input(0); Fluid blue = input(1); Fluid green = mix(yellow, blue); out[0] = yellow; out[1] = mix(yellow, green); out[2] = green; out[3] = mix(blue, green); out[4] = blue; 2. Fluid Re-Generation

26 Abstraction 3: Arbitrary Mixing Allows mixing fluids in any proportion, not just 50/50 –Fluid mix (Fluid F 1, float p 1, Fluid f 2, float F 2 )  Returns Fluid that is p 1 parts F 1 and p 2 parts F 2 –Runtime system translates to 50/50 mixes in Fluidic ISA –Note: some mixtures only reachable within error tolerance  Fluid[] out = new Fluid[8]; Fluid yellow = input (0); Fluid blue = input (1); out[0] = yellow; out[1] = mix(yellow, 3/4, blue, 1/4); out[2] = mix(yellow, 1/2, blue, 1/2); out[3] = mix(yellow, 1/4, blue, 3/4); out[4] = blue; 3. Arbitrary Mixing Fluid[] out = new Fluid[8]; Fluid yellow = input(0); Fluid blue = input(1); Fluid green = mix(yellow, blue); out[0] = yellow; out[1] = mix(yellow, green); out[2] = green; out[3] = mix(blue, green); out[4] = blue; 2. Fluid Re-Generation

27 Abstraction 3: Arbitrary Mixing Fluid[] out = new Fluid[8]; Fluid yellow = input (0); Fluid blue = input (1); for (int i=0; i<=4; i++) { out[i] = mix(yellow, 1-i/4, blue, i/4); } Allows mixing fluids in any proportion, not just 50/50 –Fluid mix (Fluid F 1, float p 1, Fluid f 2, float F 2 )  Returns Fluid that is p 1 parts F 1 and p 2 parts F 2 –Runtime system translates to 50/50 mixes in Fluidic ISA –Note: some mixtures only reachable within error tolerance  4. Parameterized Mixing Fluid[] out = new Fluid[8]; Fluid yellow = input (0); Fluid blue = input (1); out[0] = yellow; out[1] = mix(yellow, 3/4, blue, 1/4); out[2] = mix(yellow, 1/2, blue, 1/2); out[3] = mix(yellow, 1/4, blue, 3/4); out[4] = blue; 3. Arbitrary Mixing

28 BioStream Protocol Language Supports all the abstractions –Automatic storage management –Re-generation of fluids –Arbitrary mixing Implemented as a Java library –Allows flexible integration with general-purpose Java code Targets microfluidic chips or auto-generated simulator Fluid yellow = input (0); Fluid blue = input (1); Fluid[] out = new Fluid[8]; for (int i=0; i<=4; i++) { out[i] = mix(yellow, 1-i/4, blue, i/4); } Fluidic ISA BioStream Library Architecture Description - Double camera(Fluid f); Microfluidic chip Microfluidic simulator Simulator Generator User Code

29 Example: Fixed-pH Reaction Fluid sample = input (0); Fluid acid = input(1); Fluid base = input(2); do { Fluid pH_test = mix(sample, 0.9, indicator, 0.1); // test pH of sample double pH = test_luminescence(pH_test); if (pH > 7.5) { // if pH too high, add acid sample = mix (sample, 0.9, acid, 0.1); } else if (pH < 6.5) { // if pH too low, add base sample = mix (sample, 0.9, base, 0.1); } wait(60); } while (detect_activity(sample)); Goal: maintain given pH throughout reaction –For in-vitro modeling of natural environment Method: periodically test, adjust pH if needed

30 Example: Fixed-pH Reaction Fluid sample = input (0); Fluid acid = input(1); Fluid base = input(2); do { Fluid pH_test = mix(sample, 0.9, indicator, 0.1); // test pH of sample double pH = test_luminescence(pH_test); if (pH > 7.5) { // if pH too high, add acid sample = mix (sample, 0.9, acid, 0.1); } else if (pH < 6.5) { // if pH too low, add base sample = mix (sample, 0.9, base, 0.1); } wait(60); } while (detect_activity(sample)); Goal: maintain given pH throughout reaction –For in-vitro modeling of natural environment Method: periodically test, adjust pH if needed Feedback-Intensive Applications: - Recursive descent search - Directed evolution - Cell isolation and manipulation - Dose/response curves - Long, complex protocols

31 Big Picture Abstraction layers enable simple, scalable hardware –Instead of custom chips, build general-purpose devices Vision for microfluidics: everyone uses a standard chip –Thousands of storage cells –Dozens of parallel mixers –Integrated support for cell manipulation, PCR, readout, etc. Vision for software: a defacto language for experimental science –You can download a colleague’s code, run it on your chip

32 Related Work Automatic generation / scheduling of biology protocols –EDNAC computer for automatically solving 3-SAT [Johnson] –Compile SAT to microfluidic chips [Landweber et al.] [van Noort] –Robot scientist: generates/tests genetic hypotheses [King et al.] –Mapping sequence graphs to grid-based chips [Su/Chakrabarty] Custom microfluidic chips for biological computation –DNA computing [Grover & Mathies] [van Noort et al.] [McCaskill] [Livstone, Weiss, & Landweber] [Gehani & Reif] [Farfel & Stefanovic] –Self-assembly [Somei, Kaneda, Fujii, & Murata] [Whitesides et al.] General-purpose microfluidic chips –Using electrowetting, with flexible mixing [Fair et al.] –Using dialectrophoresis, with retargettable GUI [Gascoyne et al.] –Using Braille displays as programmable actuators [Gu et al.]

33 Conclusions End-to-end system for programmable microfluidics –Usable: high-level code is natural expression of protocol –Portable: same code executes on diverse chips –Scalable: protocols automatically utilize parallel resources Relies on abstraction layers –Fluidic ISA –BioStream language Future work –Incorporate stateful molecules, cells into abstraction layers –Looking for killer applications! http://cag.csail.mit.edu/biostream

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